Blocking pathway overcomes tumor vessel resistance to radiation

(NASHVILLE, Tenn., August 26, 2002) Blocking a specific signalling pathway with drugs can make blood vessels more susceptible to the effects of radiation and improve tumor control, Vanderbilt-Ingram Cancer Center scientists have demonstrated.

The study, published in the current issue of the journal Cancer Research, shows a potential way to overcome an ironic discovery found in the study. The radiation therapy intended to kill the blood vessels that feed cancer cells can actually trigger a chemical pathway that makes the vessels more resistant to therapy.

"We know that if vascular endothelium is destroyed, tumor control can be improved," said principal investigator Dr. Dennis Hallahan, chairman of Radiation Oncology. "However, the blood vessels are often resistant to the therapy. Our initial hypothesis was that the cell survival pathways that allowed the blood vessels to survive were activated by growth factors from the tumor cells. We were surprised to find that cell survival pathways were activated not only by these growth factors but by the therapy itself." Blood vessels probably developed this mechanism, Hallahan said, to protect themselves against the day-to-day exposure to so-called "free radicals" produced as a byproduct of inflammation and other normal biologic processes.

The researchers found that radiation activates a biochemical signalling pathway involving the proteins known as PI3K and Akt. This pathway then makes the endothelial cells lining the blood vessels resistant to radiation by activating a cell survival pathway. "We tested whether we could reverse the blood vessels' resistance to radiation therapy by inhibiting this pathway," Hallahan said. "We found inhibitors made tumor blood vessels more sensitive to radiation."

The scientists investigated two selective enzyme inhibitors that target this pathway, wortmannin and LY294002. In cell cultures, the researchers found that use of these drugs enhanced radiation-induced c

Contact: Cynthia Manley
Vanderbilt University Medical Center

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